Atopic dermatitis is a chronic inflammatory skin disorder exhibited by individuals with a hereditary predisposition to a lowered cutaneous threshold to pruritis, often accompanied by allergic rhinitis, hay fever, and asthma, and primarily characterized by extreme itching, leading to scratching and rubbing that in turn results in the typical lesions of eczema. In infants (infantile eczema), there is a predilection for occurrence of the cheeks, which may extend to other areas of the body; in children, adolescents and adults, it is found chiefly on the flexural surfaces (flexural eczema), especially on the antecubital and popiteal areas, and on the neck, eyelids, and wrists and behind the ears.
In atopic dermatitis, and eczema in general, immunologically mediated leukocyte infiltration (particularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin significantly contributes to the pathogenesis of these diseases. Chronic eczema also is associated with significant hyperproliferation of the epidermis.
Atopic dermatitis and eczema, if sufficiently severe, can lead to death. Less serious, but uncomfortable and often painful symptoms associated with atopic dermatitis include itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or oozing of fluid involving the skin, eye, or mucosal membranes.
The need to control atopic dermatitis has led to a search for therapeutic agents that are both safe and effective. Corticosteroids, when administered systemically, are effective in this regard but are associated with significant and potentially dangerous side effects. Topically applied corticosteroids have some efficacy in treating these conditions, but are only partially effective in many instances and have their own significant side effects, including atrophy of tissue, formation of telangiectasia, blanching, and a myriad of systemic effects if significantly absorbed. Other agents with partial utility for treating some of the above conditions include psoralen plus ultraviolet A (PUVA), cyclosporin A, ultraviolet A (UVA) and topical Doxepin, for treatment of the associated symptom of pruritis (itch), but the risk-to-benefit ratios for these agents are unfavorable for most of the conditions described above.
As a result, there is a significant and very long-standing need to identify new agents with favorable benefit to risk ratios that can be applied topically or given systemically to prevent or suppress (i.e. "treat") atopic dermatitis and its associated symptom of itch (pruritis). Optimally, such agents should be effective when administered locally or systemically, and systemic absorption should not result in blood levels high enough to cause significant systemic toxicity or other adverse side effects.
There are several conditions related to atopic dermatitis, such as hayfever, asthma and rheumatoid arthritis. It would be useful to have a method that treats these disorders as well as atopic dermatitis.
It is therefore an object of the present invention to provide methods for treating atopic dermatitis and pruritis.
It is another object of the present invention to provide methods for systemic treatment of atopic dermatitis and pruritis.
It is yet another object of the present invention to provide method for topical or transdermal treatment of atopic dermatitis and pruritis.
It is still a further object of the present invention to provide a method for treating conditions related to atopic dermatitis, such as hayfever, asthma, and rheumatoid arthritis.